Levodopa therapy monitoring in patients with Parkinson disease: a kinetic-dynamic approach

The authors assessed differences in both therapeutic and dyskinesia-matched concentrations of levodopa by kinetic-dynamic modeling in a large cohort o f patients with Parkinson disease grouped by severity of symptoms. The goal was to provide kinetic-dynamic approach to levodopa therapy monitoring to assist treating physicians in rationalizing patients' drug schedules in lin e with disease progression. Eighty-six patients, grouped according to Hoehn & Yahr (H&Y) clinical stage (H&Y I, n = 23; II, n = 25; III; n = 25; IV, n = 13) enrolled in the study. After a 12-hour levodopa washout each patient was examined using a standard oral levodopa test, based on simultaneous se rial measurements of plasma levodopa concentrations, finger-tapping motor e ffects, and dyskinesia ratings. The kinetic-dynamic modeling for both effec ts was carried out according to the "link" effect compartment model and sig moidal pharmacodynamic model. Levodopa plasma kinetics did not differ among patient groups. Duration of motor response was significantly (p < 0.001) c urtailed in patients in advanced clinical stages whereas dyskinesia duratio n showed minor changes among the three affected groups (H&Y II, III, and IV ). Median effective concentrations (EC50) were increased at the more advanc ed clinical stage (p < 0.001), from a median 0.2 mug/mL in patients at H&Y stage I to 0.9 mug/mL in patients at H&Y stage IV, whereas the maximum effe ct showed less consistent changes among the four groups. Intrasubject levod opa therapeutic concentrations were lower than values for dyskinesias in pa tients at the moderate stage of the disease, equaling dyskinesia-matched dr ug concentrations in the more affected patients. These findings are in line with previous observations of major changes in levodopa concentration-effe cts relationship with disease progression and support a stratification of p atients with Parkinson disease according; to kinetic-dynamic modeling. From a practical point of view, knowledge of individual patients' kinetic-dynam ic variables can help the physician assess patients' clinical needs objecti vely and optimize levodopa dosing according to disease progression.